ABSTRACT _____ ________________________ ______________ _____ _ Sickle cell disease (SCD) is an inherited blood disorder with several neurological and developmental complications. While there has been progress in terms of screening and treatment of neurological complications, particularly in terms of overt ischemic stroke and silent cerebral infarct, children with SCD still have worsening cognition over time in the absence of obvious brain injury. Children with SCD and attention deficit hyperactivity disorder (ADHD) and no prior history of stroke or silent cerebral infarct, defined as cryptogenic ADHD, represent an understudied yet important subset of this vulnerable population. We hypothesize that cryptogenic ADHD is associated with white matter injury and plasma biomarkers associated with brain injury. We will explore this hypothesis through the following Specific Aims. Aim 1: Identify clinical risk factors of cryptogenic ADHD in SCD. Through a retrospective chart review of patients from pediatric SCD neurodevelopmental and hematology clinics, we will compare the clinical characteristics of children with SCD and cryptogenic ADHD to children with SCD and no prior history of stroke, silent cerebral infarct, or ADHD and other neurodevelopmental disorders. Aim 2: Establish associations between cryptogenic ADHD and white matter brain injury. We will recruit 20 children 8 to 12 years of age with SCD and cryptogenic ADHD and 20 children with SCD without a prior history of stroke, silent cerebral infarct, or ADHD and other neurodevelopmental disorders to participate in a case control study. Subjects will undergo neurodevelopmental and neuropsychological evaluations, neuroimaging protocols including DTI, arterial spin labeling, oxygen extraction fraction, and volumetric imaging, and blood sample draw. Aim 3: Establish associations between cryptogenic ADHD and plasma biomarkers. Using the blood samples from the group of research subjects in Aim 2, we will measure the levels of various neuronal and glial protein markers to identify potential plasma biomarker proteins of neurological injury. We will compare the protein levels to DTI findings as well as neuropsychological measures. The proposed work will define a clinical and neuroimaging phenotype of children with SCD and cryptogenic ADHD, establishing this population as part of the spectrum of brain injury seen in pediatric SCD. The Principal Investigator will require additional training in the hematological management of SCD and neuroimaging acquisition and analysis techniques to complete the proposed projects. Future research will involve use of DTI as a measure of disease severity, predict cognitive outcomes, and monitor response to treatment in clinical trials research and longitudinal assessment of the research group established in Aim 2 to establish their risk of future neurological complications.